High Shear Granulation Scale-Up

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• High Shear Granulation Scale-Up
• Mohsen Sadatrezaei Pharm.D.
• SANDOZ USA
• Dayton, NJ

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Introduction

• Wet granulation is used to improve . . .
• Flow
• Compressibility
• Bio-availability
• Homogeneity
• Electrostatic properties
• Stability

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Factors in High shear wet granulation

• Densification
• Agglomeration
• Shearing and compressing action of the impeller
• Mixing, granulation and wet massing
• Possibility of overgranulation due to excessive
  wetting
• Possibility of producing low porosity granules
• Liquid bridges
• Coalescence
• Breakage of the bonds
• Specific surface area
• Moisture content
• Intragranular porosity
• Heating
• Evaporation
• Mean granule size

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Granule Growth

• Granule formation and growth can be described by
  two mechanisms
• Nucleation of particles
• Coalescence between agglomerates

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Coalescence

• Plastic deformation upon collision
• Surface water
• Absolute moisture content vs. Liquid
  saturation

H (1 e) ? S e
H Moisture content on dry basis e Granular
porosity ? Particle density of the feed
material
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Granule growth in high shear mixer
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Effect of feed material on Granule growth in
high shear mixer
From Hand book of Pharmaceutical granulation
Page 162
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Granule growth in high shear mixer

• This demonstrates the characteristic features of
  the agglomeration of insoluble, cohesive powders
  in high shear mixers. The growth rate is very
  sensitive to the amount of liquid phase and to
  processing conditions, in particular the impeller
  rotation speed and processing time.

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Granulation process development of a cohesive,
fine, water insoluble material
Decreasing Intragranular porosity
Kneading phase (7 minutes)
Liquid addition phase (3 minutes)
Granule growth by nucleation
Coalescence/Densification
Critical moisture content
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High shear Granulation

• Granulation properties are influenced by
• Apparatus variables
• Process variables
• Product variables

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Apparatus variables

• Shear forces in a high shear mixer are very
  dependent on the mixer construction
• Bowl design
• Impeller design
• Chopper design

• While the fluidized state in a fluidized bed
  granulator is nearly independent of the
  construction of the apparatus, shear forces in a
  high shear mixer are very dependent on the mixer
  construction. Consequently, apparatus variables
  are more essential when using high shear mixers.
  Size and shape of the mixing chamber, impeller
  and chopper differ in different high shear mixers.

• A small change in shape, size or inclination of
  the blade tips have a significant effect on the
  impact of the mass.

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Apparatus variables

• Relative Swept volume The volume swept out per
  second by the impellor divided by the volume of
  the mixer.
• The relative swept volume has considered to
  relate to the work input on the material which is
  assumed to provide densification of the wet mass.

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Relative swept volume
From Pharm. Ind. 48, 1083 (1986)

• The relative swept volume seems to be an
  appropriate parameter when comparing the effect
  of size and construction of the mixing tools.

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Process Variables

• Impeller rotation speed
• Chopper rotation speed
• Load of the mixer
• Liquid addition method
• Liquid flow rate
• Wet massing time

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Product variables

• Characteristics of the feed materials
• Particle size and size distribution
• Solubility in the liquid binder
• Wettability
• Packing properties
• Amount of liquid binder
• Characteristics of liquid binder
• Surface tension
• Viscosity

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Granulation end point
What is the end point? When you stop your mixer!

• Target particle size mean
• Target particle size distribution
• Target granule viscosity
• Target granule density
• Principle of equifinality

• Determining the end point, and then
  reproducibility arriving at that same end point
  as equipment size and model changes are
  encountered, has been a continual challenge for
  the formulation scientist

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Granulation End Pointand Product Properties
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Granulation end point determination

• Hand test
• Qualitative
• Subjective
• Inconsistent
• Emerging methods
• Acoustic Emission (Int. J. Pharm 205, 2000 79
  71)
• Image processing (Powder Tech. 115, 2001 124
  130)
• Off line methods
• Torque Rheology (Mass consistency)
• Granulation particle size
• In line instrumentation
• Main impeller motor amperage
• Main impeller motor power
• Main impeller shaft torque

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Typical Power and Torque Curves
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Benefits of Mixer Instrumentation

• Machine troubleshooting
• Formulation fingerprints
• Batch reproducibility
• Process optimization
• Process scale-up

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Forces in high shear Granulation

• Acceleration F1
• Frictional F2
• Centripetal F3
• Centrifugal F4

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Forces in high shear Granulation
From Hand book of granulation technology page191
The data on centrifugal acceleration reveal that
one might expect higher compaction forces in
smaller machines at the same level of tip speed.
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scale-up approach 1 from Horsthius et al.(1993)

• relative swept volume
• blade tip speed
• Froude number

Fr n2 d / g
n - impeller speed T-1 d - impeller diameter
L g - gravitational constant LT-2
They concluded that maintaining an equal Froudes
number at different scales resulted in comparable
particle size distribution.
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Use of Froude Numbers for mixers comparison

• Froude number
• Being dimensionless it is independent of
  machine size
• Ratio of centrifugal force to gravitational
  force
• Can be a criterion of dynamic similarity of
  mixers

In a recent publication by Michael Levin
different mixers have been compared by the range
of Froude number they can produce. A matching
range of Froude numbers would indicate the
possibility of scale-up even for the mixers that
are not geometrically similar.
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Use of Froude Numbers for mixer comparisons
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Use of Froude Numbers for mixer comparisons
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Use of Froude Numbers for mixer comparisons
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scale-up approach 2 from Rekhi et al. (1996)

• Constant impeller tip speed
• Granulating liquid volume proportional to batch
  size
• Wet massing time inversely proportional to RPM

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PMA mixers characteristics
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scale-up approach 3, Using power number
correlations Landin, M., P. York, M.J.
Cliff(1996)

• Dependent of the concept of similarity
• Geometric similarity
• All corresponding dimensions have same ratio
• Kinematic similarity
• All velocities at corresponding points have same
  ratio
• Dynamic similarity
• All forces at corresponding points have same
  ratio

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scale-up approach 3, Using power number
correlations
Dimensionless numbers
Ne P / (? n3 d5) Newton (power) Fr n2 d
/ g Froude Re d2 n ? / ? Reynolds
P - power consumption ML2T-5 ? - specific
density of particles M L-5 n - impeller speed
T-1 d - impeller diameter L g -
gravitational constant LT-2 ? - dynamic
viscosity M L-1 T-1

• Being dimensionless, the relationship becomes
  general for a series of geometrically similar
  high shear mixers regardless of their scale.

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scale-up approach 3, Using power number
correlations
Power number relationship

• Ne K(Re.Fr. h/D)n h height of powder bed
• D Diameter

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scale-up approach 3, Using power number
correlations
Experimental procedure

• Charge powders and switch on mixer
• Note power reading
• Add water at constant rate
• At specific water contents note power reading
  and take sample
• Measure density of sample
• Measure viscosity of sample
• Calculate Power, Reynolds and Froude numbers
• Plot Power number relationship

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scale-up approach 3, Using power number
correlations
scale-up strategy

• Perform experiments on small scale to define
  master curve for the formulation
• Identify viscosity and density of wet mass that
  produces optimum granules
• Use these values plus machine variables to
  calculate power needed on desired large scale
  mixer
• Run large scale mixer at the defined setting
• Check mass using the mixer torque rheometer

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Conclusion/Recommendations

• Design a process friendly formulation.
• Make sure the process on the small scale is
  understood controlled.
• Attempt to develop formulation/process in the
  same mixer model as the production scale
  (Geometric similarity)
• Use the Froude number as an indication of the
  possibility of scale-up between two different
  mixer.
• Try to work with slow impeller speed during
  development work in the lab scale mixers to
  simulate production scale mixers.
• Use relative swept volume as a good indication of
  how much work will be done on the granulate.
• Establish an END POINT based on a reliable
  response factor and characterize the granulation
  and tablet properties at the same end point.
• Do an intentional overgranulation and
  undergrnulation and characterize
  granulation/tabletting properties.
• In most cases Granulation liquid can be scaled up
  linearly.
• Try to keep the mixer load ratio consistent in
  the small and large scale mixers.

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Comments Questions?